The high proliferation rate of cancer cells is a result not only of decreased cell death but also of improperly regulated cell cycling, allowing evasion of growth suppressing signals. Although multiple cell cycle checkpoints can be impaired in cancer, the mitotic or spindle assembly checkpoint is of great importance both in tumorigenesis and as an anticancer target. This point of regulation, which is responsible for ensuring appropriate chromosome segregation, is required for cell viability. Cells with a weakened mitotic checkpoint are capable of survival but do not maintain proper chromosome segregation, resulting in genomic instability and aneuploidy. PARP (poly(ADP-ribose) polymerase) is an important protein in DNA repair pathways especially the base excision repair (BER). BER is involved in DNA repair of single strand breaks (SSBs). If BER is impaired, inhibiting PARP, SSBs accumulate and become double stand breaks (DSBs). In addition, PARP can act on many mediators of cell cycle progression through its effects on gene expression. However, direct regulation of the mitotic checkpoint by PARP is another important factor that may be exploited in the development of an optimal cancer therapy.
Recent reports suggest multiple roles for PARP in the structural machinery of mitosis. First, PAR, which is primarily synthesized by PARP, is required for assembly and function of the bipolar spindle. In addition, PARP-1 both localizes to and PARylates proteins at centromeres and centrosomes during mitosis. PARP-1 also mediates PARylation of p53, which is responsible for regulating centrosome duplication and monitoring chromosomal stability. Loss of PARP activity is incomplete synapsis of homologous chromosomes, defective chromatin modifications, and failure to maintain metaphase arrest, indicating loss of mitotic checkpoint integrity. Similarly, inhibition of PARP-1 is associated with genomic instability characterized by reduced stringency of mitotic checkpoints, centrosome hyper-amplification, and chromosomal aneuploidy. Furthermore, PARP-1 has been shown to interact with the E3 ubiquitin ligase, CHFR, a tumor suppressor with an important role in the early mitotic checkpoint. Binding of these two proteins results in cell cycle arrest in prophase, an effect stimulated by microtubule inhibitors resulting in resistance to this class of drugs in cancer cells. Thus, inhibition of PARP or microtubules, or both, could significantly increase cancer cells death, and may be a promising anti-cancer strategy.
The present invention relates to compounds having microtubule-perturbing and/or anti-PARP activity. These compounds may be used for treatment in the animal of a disease associated with tubulin polymerization or PARP, or both. This, and other uses of these compounds are described herein.